Ageing and neurotrophic signalling effects on diaphragm neuromuscular function

Sarcopenia of the diaphragm muscle, i.e. loss of muscle force and size with increasing age, may contribute to respiratory impairment in old age but the exact mechanisms underlying this are currently unknown. Across the lifespan in mice there is worsening neuromuscular function of the diaphragm muscle, specifically reduced force and impaired neuromuscular transmission. We tested the hypothesis that age‐related changes to the diaphragm muscle depend on brain‐derived neurotrophic factor (BDNF), acting through its high affinity receptor. BDNF improves neuromuscular transmission in the diaphragm muscle into early old age, but not older ages. Inhibition of BDNF signalling impairs neuromuscular transmission only in young adult mice. Our results suggest that the loss of endogenous BDNF precedes reduced activity of the high affinity receptor tropomyosin‐related kinase receptor B in the ageing mouse diaphragm muscle.

[1]  C. Mantilla,et al.  TrkB kinase activity is critical for recovery of respiratory function after cervical spinal cord hemisection , 2014, Experimental Neurology.

[2]  M. Riva,et al.  Reduced neuroplasticity in aged rats: a role for the neurotrophin brain-derived neurotrophic factor , 2013, Neurobiology of Aging.

[3]  Sarah M. Greising,et al.  Diaphragm muscle sarcopenia in aging mice , 2013, Experimental Gerontology.

[4]  C. Mantilla,et al.  Novel method for transdiaphragmatic pressure measurements in mice , 2013, Respiratory Physiology & Neurobiology.

[5]  K. Personius,et al.  TrkB expression at the neuromuscular junction is reduced during aging , 2013, Muscle & nerve.

[6]  J. Sanes,et al.  Shared Resistance to Aging and ALS in Neuromuscular Junctions of Specific Muscles , 2012, PloS one.

[7]  M. Frotscher,et al.  Jcb: Article , 2022 .

[8]  C. Mantilla,et al.  The novel TrkB receptor agonist 7,8‐dihydroxyflavone enhances neuromuscular transmission , 2012, Muscle & nerve.

[9]  C. Mantilla,et al.  Structure–activity relationships in rodent diaphragm muscle fibers vs. neuromuscular junctions , 2012, Respiratory Physiology & Neurobiology.

[10]  Chao Zhang,et al.  Genetic deletion of trkB.T1 increases neuromuscular function. , 2012, American journal of physiology. Cell physiology.

[11]  K. Personius,et al.  Reduced TrkB expression results in precocious age-like changes in neuromuscular structure, neurotransmission, and muscle function. , 2011, Journal of applied physiology.

[12]  Melonie P. Heron,et al.  Deaths: leading causes for 2007. , 2011, National vital statistics reports : from the Centers for Disease Control and Prevention, National Center for Health Statistics, National Vital Statistics System.

[13]  C. Mantilla,et al.  Age-related remodeling of neuromuscular junctions , 2011 .

[14]  N. Besalduch,et al.  The Interaction between Tropomyosin-Related Kinase B Receptors and Presynaptic Muscarinic Receptors Modulates Transmitter Release in Adult Rodent Motor Nerve Terminals , 2010, The Journal of Neuroscience.

[15]  Carlos B. Mantilla,et al.  Diaphragm motor unit recruitment in rats , 2010, Respiratory Physiology & Neurobiology.

[16]  M. Deschenes,et al.  Remodeling of the neuromuscular junction precedes sarcopenia related alterations in myofibers , 2010, Experimental Gerontology.

[17]  C. Mantilla,et al.  Impairment of diaphragm muscle force and neuromuscular transmission after normothermic cardiopulmonary bypass: effect of low-dose inhaled CO. , 2010, American journal of physiology. Regulatory, integrative and comparative physiology.

[18]  N. Besalduch,et al.  Localization of brain‐derived neurotrophic factor, neurotrophin‐4, tropomyosin‐related kinase b receptor, and p75NTR receptor by high‐resolution immunohistochemistry on the adult mouse neuromuscular junction , 2010, Journal of the peripheral nervous system : JPNS.

[19]  C. Mantilla,et al.  Neuromuscular adaptations to respiratory muscle inactivity , 2009, Respiratory Physiology & Neurobiology.

[20]  C. Mantilla,et al.  Neuromuscular Junction (NMJ): Aging , 2009 .

[21]  C. Mantilla,et al.  Trophic factor expression in phrenic motor neurons , 2008, Respiratory Physiology & Neurobiology.

[22]  J. Ribeiro,et al.  Triggering of BDNF facilitatory action on neuromuscular transmission by adenosine A2A receptors , 2006, Neuroscience Letters.

[23]  Xi Chen,et al.  A Chemical-Genetic Approach to Studying Neurotrophin Signaling , 2005, Neuron.

[24]  C. Mantilla,et al.  Neurotrophins improve neuromuscular transmission in the adult rat diaphragm , 2004, Muscle & nerve.

[25]  B. Lu.  Acute and long-term synaptic modulation by neurotrophins. , 2004, Progress in brain research.

[26]  E. Huang,et al.  Trk receptors: roles in neuronal signal transduction. , 2003, Annual review of biochemistry.

[27]  R. Vandenboom,et al.  Power fatigue of the rat diaphragm muscle. , 2000, Journal of applied physiology.

[28]  N. Nadon,et al.  Principles of Animal Use for Gerontological Research , 2000, The journals of gerontology. Series A, Biological sciences and medical sciences.

[29]  B. Hass,et al.  Growth curves and survival characteristics of the animals used in the Biomarkers of Aging Program. , 1999, The journals of gerontology. Series A, Biological sciences and medical sciences.

[30]  M. Rich,et al.  Disruption of TrkB-Mediated Signaling Induces Disassembly of Postsynaptic Receptor Clusters at Neuromuscular Junctions , 1999, Neuron.

[31]  B. Ulfhake,et al.  Reciprocal changes in the expression of neurotrophin mRNAs in target tissues and peripheral nerves of aged rats , 1999, Neuroscience Letters.

[32]  T. Hökfelt,et al.  Expression of p75(NTR), trkB and trkC in nonmanipulated and axotomized motoneurons of aged rats. , 1999, Brain research. Molecular brain research.

[33]  H. Miyata,et al.  Inactivity‐induced remodeling of neuromuscular junctions in rat diaphragmatic muscle , 1999, Muscle & nerve.

[34]  G. Sieck,et al.  Age‐related remodeling of neuromuscular junctions on type‐identified diaphragm fibers , 1998, Muscle & nerve.

[35]  V. Suman,et al.  Risk factors for 30-day mortality in elderly patients with lower respiratory tract infection. Community-based study. , 1997, Archives of internal medicine.

[36]  G. Sieck,et al.  Hypothyroid-mediated changes in adult rat diaphragm muscle contractile properties and MHC isoform expression. , 1996, Journal of applied physiology.

[37]  C F Ibáñez,et al.  Muscle-derived neurotrophin-4 as an activity-dependent trophic signal for adult motor neurons. , 1995, Science.

[38]  G. Sieck,et al.  Fatigue at the Neuromuscular Junction , 1995 .

[39]  G. Sieck,et al.  Fatigue at the neuromuscular junction. Branch point vs. presynaptic vs. postsynaptic mechanisms. , 1995, Advances in experimental medicine and biology.

[40]  M. Reid,et al.  Dimethyl sulfoxide depresses skeletal muscle contractility. , 1994, Journal of applied physiology.

[41]  M. Niederman,et al.  Severe pneumonia in the elderly. , 1994, Clinics in geriatric medicine.

[42]  G. Sieck,et al.  Differential susceptibility of diaphragm muscle fibers to neuromuscular transmission failure. , 1993, Journal of applied physiology.

[43]  G. Sieck,et al.  Neuromuscular transmission failure during postnatal development , 1991, Neuroscience Letters.

[44]  R. Shadmehr,et al.  Relative contribution of neurotransmission failure to diaphragm fatigue. , 1990, Journal of applied physiology.

[45]  G. Sieck.  Diaphragm muscle: structural and functional organization. , 1988, Clinics in Chest Medicine.

[46]  G. Sieck,et al.  Effect of nutritional deprivation on diaphragm contractility and muscle fiber size. , 1986, Journal of applied physiology.

[47]  M. Fahim,et al.  Scanning and light microscopic study of age changes at a neuromuscular junction in the mouse , 1983, Journal of neurocytology.

[48]  M. Fahim,et al.  Ultrastructural studies of young and old mouse neuromuscular junctions , 1982, Journal of neurocytology.

[49]  Dean O. Smith.  Reduced capabilities of synaptic transmission in aged rats , 1979, Experimental Neurology.